Bicyclic 4-aralkylaminopyrimidine derivatives as tyrosine kinase inhibitors

ABSTRACT

Novel and known bicyclic 4-aralkylaminopyrimidine derivatives of formula (I) wherein A is a benzene or imidazole ring; B is a benzene, tetralin, indane or 2-oxindole ring R is (C 1  -C 4 )perfluoroalkyl, phenyl, phenyl-(C 1  -C 4 )alkyl, hydroxy-(C 1  -C 4 )alkyl, (C 1  -C 4 )alkoxy-(C 1  -C 4 )alkyl, (C 2  -C 4 )acyloxy-(C 1  -C 4 )alkyl, halobenzoyloxy-(C 1  -C 4 )alkyl, carboxy, carbamoyl, (C 1  -C 4 )alkoxycarbonyl, cyano, (C 1  -C 4 )alkylcarbonyl, carboxy-(C 1  -C 4 )alkyl, carbamoyl-(C 1  -C 4 )alkyl, (C 1  -C 4 )alkoxycarbonyl-(C 1  -C 4 )alkyl, halo-(C 1  -C 4 )alkyl, amino-(C 1  -C 4 )alkyl, mono- or di-(C 1  -C 4 )alkylamino-(C 1  -C 4 )alkyl, sulfo-(C 1  -C 4 )alkyl or sulfamido-(C 1  -C 4 )alkyl; each of R 1  and R 2 , which may be the same or different, is hydrogen, C 1  -C 4  alkyl, C 1  -C 4  alkoxy, halogen or --NR 5  R 6  in which each of R 5  and R 6 , which may be the same or different, is H or C 1  -C 4  alkyl; each of R 3  and R 4 , which may the same or different, is hydrogen, C 1  -C 4  alkyl, halogen, hydroxy, C 1  -C 4  alkoxy, C 1  -C 4  alkoxycarbonyl, nitro, cyano or CF 3  ; and the pharmaceutically acceptable salts thereof, are tyrosine kinase inhibitors. ##STR1##

This application is a 371 of PCT/EP97/02965, filed Jun. 3, 1997.

The present invention relates to novel and known bicyclic4-aralkylaminopyrimidine derivatives, to a process for theirpreparation, to pharmaceutical compositions containing them and to theiruse as therapeutic agents, in particular as tyrosine kinase inhibitors.

Several N-substituted 4-aminopyrimidines are known in the art. Forinstance Japanese patent application JP92-270490 (C.A. 122: 133208)discloses the preparation of N-substituted 4-amino-pyrimidinederivatives useful as agrochemical fungicides, insecticides, nematocidesand acaricides. French patent no. 1438006 (C.A.66: 11176e) claims6-substituted purine compounds having kinetine activity. EP-A-0390112discloses purine and pyrazolo-pyrimidine compounds which are selectiveadenosine receptor agents in particular adenosine antagonists.Phytochemistry 10(1), 23-8, 1971; and ibidem, 7(11), 1989-94, 1968relate to cytokinin activity of substituted purines in plants. DE4321029 (C.A.122: 160674) teaches the preparation of 4-substitutedquinazolineamines useful as agrochemical fungicides.

The present invention provides, as a first aspect, the use of a compoundhaving the following formula (I) ##STR2## wherein A is a benzene orimidazole ring;

B is a benzene, tetralin, indane or 2-oxindole ring;

R is (C₁ -C₄) perfluoroalkyl, phenyl, phenyl-(C₁ -C₄)alkyl, hydroxy-(C₁-C₄)alkyl, (C₁ -C₄)alkoxy-(C₁ -C₄)alkyl, (C₂ -C₄)acyloxy-(C₁ -C₄)alkyl,halobenzoyloxy-(C₁ -C₄)alkyl, carboxy, carbamoyl, (C₁-C₄)alkoxycarbonyl, cyano, (C₁ -C₄)alkylcarbonyl, carboxy-(C₁ -C₄)alkyl,carbamoyl-(C₁ -C₄)alkyl, (C₁ -C₄)alkoxycarbonyl-(C₁ -C₄)alkyl, halo-(C₁-C₄)alkyl, amino-(C₁ -C₄)alkyl, mono- or di-(C₁ -C₄)alkylamino-(C₁-C₄)alkyl, sulfo-(C₁ -C₄)alkyl or sulfamido-(C₁ -C₄)alkyl;

each of R₁ and R₂, independently, is hydrogen, C₁ -C₄ alkyl, C₁ -C₄alkoxy, halogen or --NR₅ R₆ in which each of R₅ and R₆ independently isH or C₁ -C₄ alkyl;

each of R₃ and R₄, independently, is hydrogen, C₁ -C₄ alkyl, halogen,hydroxy, C₁ -C₄ alkoxy, C₁ -C₄ alkoxycarbonyl, nitro, cyano or CF₃ ; ora pharmaceutically acceptable salt thereof, for the manufacture of amedicament for use as tyrosine kinase inhibitor.

It is evident to the people skilled in the art that when at the sametime ring A is imidazole and one of R₁ and R₂ is C₁ -C₄ alkoxy, halogenor --NR₅ R₆ then such substituent is only linked to the carbon ringatoms of the imidazole moiety. Whereas when the substituents R₁ and R₂are C₁ -C₄ alkyl they may be attached either to the carbon or nitrogenring atoms of the imidazole moiety.

When the ring B is tetralin, indane or 2-oxindole the aminomethyl bridgemay be located on either of the ring B moieties, preferably it islocated on the benzene moiety.

The R₃ and R₄ substituents in tetralin and indane may be on either ofthe ring moieties, preferably they are attached to the benzene moiety.In 2-oxindole the R₃ and R₄ substituents can be located on the benzenemoiety, whereas the C₁ -C₄ alkyl substituent may also be attached to thenitrogen ring atom of the pyrrole moiety, of course.

When in the synthesis optically active aralkylamino derivatives areemployed, then the R substituent may be above or beneath the planeindicating an (R) or (S) configuration.

The invention includes within its scope all the possible isomers,stereoisomers and their mixtures, and the metabolites and the metabolicprecursors or bio-precursors (otherwise known as prodrugs) of thecompounds of formula (I).

An alkyl group or an alkyl moiety in a alkoxy, alkylcarbonyl oralkoxycarbonyl group may be a branched or straight alkyl chain.

A C₁ -C₄ alkyl group is preferably a C₁ -C₂ alkyl, that is ethyl ormethyl.

A C₁ -C₄ alkoxy group is preferably a methoxy or ethoxy group.

A C₁ -C₄ alkylcarbonyl is preferably an acetyl.

A (C₁ -C₄)perfluoralkyl is preferably a trifluoromethyl.

A phenyl-(C₁ -C₄)alkyl is preferably benzyl.

A hydroxy-(C₁ -C₄)alkyl is preferably hydroxymethyl.

A (C₁ -C₄)alkoxy-(C₁ -C₄)alkyl is preferably methoxymethyl.

An (C₂ -C₄)acyloxy-(C₁ -C₄)alkyl is preferably acetoxymethyl.

A halobenzoyloxy-(C₁ -C₄)alkyl is preferably a bromobenzoyloxy-(C₁-C₄)alkyl, in particular, bromobenzoyloxymethyl.

A (C₁ -C₄)alkoxycarbonyl is preferably carbomethoxy.

A halo-(C₁ -C₄)alkyl is preferably chloromethyl.

A mono-(C₁ -C₄)alkylamino-(C₁ -C₄)alkyl is preferably methylaminomethyl.

A di-(C₁ -C₄)alkylamino-(C₁ -C₄)alkyl is preferably dimethylaminomethyl.

A sulfamido-(C₁ -C₄)alkyl is preferably sulfamidomethyl.

A halogen atom is for example fluoro, chloro, bromo or iodio, inparticular bromo or fluoro.

Pharmaceutically acceptable salts of the compounds of the i inventioninclude acid addition salts with inorganic acids, e.g. nitric,hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric acid ororganic acids, e.g. acetic, trifluoracetic, propionic, glycolic, lactic,oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic,mandelic and salicylic acid. The salts with inorganic bases include e.g.alkali metal, especially sodium or potassium bases, or earth alkalimetal, especially calcium or magnesium bases, or with organic bases,e.g. alkylamines, preferably triethylamine.

As stated above, the present invention also includes within its scopepharmaceutically acceptable bio-precursors [otherwise known as prodrugsof the compounds of formula (I)], i.e. compounds which have differentformula to formula (I) above but which, nevertheless, uponadministration to a human being are converted directly or indirectly invivo into a compound of formula (I).

Preferred compounds of the invention are the compounds of formula (I),wherein

A is a benzene or imidazole ring;

B is a benzene or tetralin ring;

R is hydroxy-(C₁ -C₄)alkyl, (C₂ -C₄)acyloxy-(C₁ -C₄)alkyl,halobenzoyloxy-(C₁ -C₄)alkyl, (C₁ -C₄)alkoxycarbonyl, di-(C₁-C₄)alkylamino-(C₁ -C₄)alkyl, trifluoromethyl or carbamoyl;

each of R₁ and R₂ independently is hydrogen or C₁ -C₄ -alkoxy;

each of R₃ and R₄ is hydrogen;

and the pharmaceutically acceptable salts thereof.

Examples of preferred specific compounds of formula (I) are thefollowing compounds:

4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(acetoxymethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(3-bromobenzoyloxymethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(trifluoromethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbamoyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbomethoxy)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(dimethylaminomethyl)benzylamino]-6,7-dimethoxyquinazoline

4-[α-(hydroxymethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(acetoxymethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(3-bromobenzoyloxymethyl)-2-tetralylmethylamino]-6,7dimethoxyquinazoline;

4-[α-(trifluoromethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbamoyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbomethoxy)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(dimethylaminomethyl)-2-tetralylmethylamino]-6,7dimethoxy-quinazoline;

6-[α-(hydroxymethyl)benzylamino]-purine;

6-[α-(acetoxymethyl)benzylamino]-purine;

6-[α-(3-bromobenzoyloxymethyl)benzylamino]-purine;

6-[α-(trifluoromethyl)benzylamino]-purine;

6-[α-(carbamoyl)benzylamino]-purine;

6-[α-(carbomethoxy)benzylamino]-purine;

6-[α-(dimethylaminomethyl)benzylamino]-purine;

6-[α-(hydroxymethyl)-2-tetralylmethylamino]-purine;

6-[α-(acetoxymethyl)-2-tetralylmethylamino]-purine;

6-[α-(3-bromobenzoyloxymethyl)-2-tetralylmethylamino]-purine;

6-[α-(trifluoromethyl)-2-tetralylmethylamino]-purine;

4-[α-(carbamoyl)-2-tetralylmethylamino]-purine;

4-[α-(carbomethoxy)-2-tetralylmethylamino]-purine; and

4-[α-(dimethylaminomethyl)-2-tetralylmethylamino]-purine;

either as single isomers or as a mixture thereof and thepharmaceutically acceptable salts thereof.

Accordingly, the present invention provides a method of treating amammal, including humans, in need of a tyrosine kinase inhibiting agent,the method comprising administering to said mammal a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient (whichcan be a carrier and/or diluent) and as an active principle a compoundof formula (IA) ##STR3## wherein A is a benzene or imidazole ring;

B is a benzene, tetralin, indane or 2-oxindole ring;

R is (C₁ -C₄) perfluoroalkyl, phenyl, phenyl-(C₁ -C₄)alkyl, hydroxy-(C₁-C₄)alkyl, (C₁ -C₄)alkoxy-(C₁ -C₄)alkyl, (C₂ -C₄)acyloxy-(C₁ -C₄)alkyl,halobenzoyloxy-(C₁ -C₄)alkyl, carboxy, carbamoyl, (C₁-C₄)alkoxycarbonyl, cyano, (C₁ -C₄)alkylcarbonyl, carboxy-(C₁ -C₄)alkyl,carbamoyl-(C₁ -C₄)alkyl, (C₁ -C₄)alkoxycarbonyl-(C₁ -C₄)alkyl, halo-(C₁-C₄)alkyl, amino-(C₁ -C₄)alkyl, mono- or di-(C₁ -C₄)alkylamino-(C₁-C₄)alkyl, sulfo-(C₁ -C₄)alkyl or sulfamido-(C₁ -C₄)alkyl;

each of R₁ and R₂, independently, is hydrogen, C₁ -C₄ alkyl, C₁ -C₄alkoxy, halogen or --NR₅ R₆ in which each of R₅ and R₆ independently isH or C₁ -C₄ alkyl ;

each of R₃ and R₄, independently, is hydrogen, C₁ -C₄ alkyl, halogen,hydroxy, C₁ -C₄ alkoxy, C₁ -C₄ alkoxycarbonyl, nitro, cyano or CF₃ ; ora pharmaceutically acceptable salt thereof, and wherein when at the sametime A is unsubstituted imidazole and B is unsubstituted phenyl, then Ris other than hydroxy-(C₁ -C₃)alkyl.

Preferred compounds of formula (IA), as defined above, are those wherein

A is a benzene or imidazole ring;

B is a benzene or tetralin ring;

R is hydroxy-(C₁ -C₄)alkyl, (C₂ -C₄)acyloxy-(C₁ -C₄)alkyl,halobenzoyloxy-(C₁ -C₄)alkyl, (C₁ -C₄)alkoxycarbonyl, di-(C₁-C₄)alkylamino-(C₁ -C₄)alkyl, trifluoromethyl or carbamoyl;

each of R₁ and R₂ independently is hydrogen or C₁ -C₄ alkoxy;

each of R₃ and R₄ is hydrogen;

and the pharmaceutically acceptable salts thereof.

Examples of preferred specific compounds of formula (IA) are thefollowing compounds:

4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(acetoxymethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(3-bromobenzoyloxymethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(trifluoromethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbamoyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbomethoxy)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(dimethylaminomethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(hydroxymethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(acetoxymethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(3-bromobenzoyloxymethyl)-2-tetralylmethylamino]-6,7dimethoxyquinazoline;

4-[α-(trifluoromethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbamoyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbomethoxy)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(dimethylaminomethyl)-2-tetralylmethylamino]-6,7dimethoxyquinazoline;

6-[α-(acetoxymethyl)benzylamino]-purine;

6-[α-(3-bromobenzoyloxymethyl)benzylamino]-purine;

6-[α-(trifluoromethyl)benzylamino]-purine;

6-[α-(carbamoyl)benzylamino]-purine;

6-[α-(carbomethoxy)benzylamino]-purine;

6-[α-(dimethylaminomethyl)benzylamino]-purine;

6-[α-(hydroxymethyl)-2-tetralylmethylamino]-purine;

6-[α-(acetoxymethyl)-2-tetralylmethylamino]-purine;

6-[α-(3-bromobenzoyloxymethyl)-2-tetralylmethylamino]-purine;

6-[α-(trifluoromethyl)-2-tetralylmethylamino]-purine;

4-[α-(carbamoyl)-2-tetralylmethylamino]-purine;

4-[α-(carbomethoxy)-2-tetralylmethylamino]-purine; and

4-[α-(dimethylaminomethyl)-2-tetralylmethylamino]-purine;

either as single isomers or as a mixture thereof and thepharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a bicyclic4-aralkylaminopyrimidine derivative of formula (IA), or apharmaceutically acceptable salt thereof, as defined above, for use asan active therapeutic substance, in particular as tyrosine kinaseinhibitor.

A further object of the invention are novel bicyclic4-aralkylaminopyrimidine derivatives having the following formula (IB)##STR4## wherein A is a benzene or imidazole ring;

B is a benzene, tetralin, indane or 2-oxindole ring;

R is (C₁ -C₄) perfluoroalkyl, phenyl, phenyl-(C₁ -C₄)alkyl, hydroxy-(C₁-C₄)alkyl, (C₁ -C₄)alkoxy-(C₁ -C₄)alkyl, (C₂ -C₄)acyloxy-(C₁ -C₄)alkyl,halobenzoyloxy-(C₁ -C₄)alkyl, carboxy, carbamoyl, (C₁-C₄)alkoxycarbonyl, cyano, (C₁ -C₄)alkylcarbonyl, carboxy-(C₁ -C₄)alkyl,carbamoyl-(C₁ -C₄)alkyl, (C₁ -C₄)alkoxycarbonyl-(C₁ -C₄)alkyl, halo-(C₁-C₄)alkyl, amino-(C₁ -C₄)alkyl, mono- or di-(C₁ -C₄)alkylamino-(C₁-C₄)alkyl, sulfo-(C₁ -C₄)alkyl or sulfamido-(C₁ -C₄)alkyl;

each of R₁ and R₂, independently, is hydrogen, C₁ -C₄ alkyl, C₁ -C₄alkoxy, halogen or --NR₅ R₆ in which each of R₅ and R₆ independently isH or C₁ -C₄ alkyl ;

each of R₃ and R₄, independently, is hydrogen, C₁ -C₄ alkyl, halogen,hydroxy, C₁ -C₄ alkoxy, C₁ -C₄ alkoxycarbonyl, nitro, cyano or CF₃ ; ora pharmaceutically acceptable salt thereof,

and wherein when at the same time, A is unsubstituted benzene orimidazole, R is hydroxyethyl, (C₁ -C₄)alkoxy-ethyl or (C₂-C₄)acyloxy-ethyl, and B is phenyl, then at least one of

R₃ and R₄ is other than hydrogen, halogen, C₁ -C₄ alkyl or C₁ -C₄alkoxy; and wherein, when at the same time A is unsubstituted imidazoleand B is unsubstituted phenyl, then R is other than carboxy orhydroxy-(C₁ -C₃)alkyl.

Preferred compounds of formula (IB), as defined above, are those wherein

A is a benzene or imidazole ring;

B is a benzene or tetralin ring;

R is hydroxy-(C₁ -C₄)alkyl, (C₂ -C₄)acyloxy-(C₁ -C₄)alkyl,halobenzoyloxy-(C₁ -C₄)alkyl, (C₁ -C₄)alkoxycarbonyl, di-(C₁-C₄)alkylamino-(C₁ -C₄)alkyl, trifluoromethyl or carbamoyl;

each of R₁ and R₂ independently is hydrogen or C₁ -C₄ alkoxy;

each of R₃ and R₄ is hydrogen;

and the pharmaceutically acceptable salts thereof.

Examples of preferred specific compounds of formula (IB) are thefollowing compounds:

4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(acetoxymethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(3-bromobenzoyloxymethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(trifluoromethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbamoyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbomethoxy)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(dimethylaminomethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(hydroxymethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(acetoxymethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(3-bromobenzoyloxymethyl)-2-tetralylmethylamino]-6,7dimethoxyquinazoline;

4-[α-(trifluoromethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbamoyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbomethoxy)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(dimethylaminomethyl)-2-tetralylmethylamino]-6,7dimethoxyquinazoline;

6-[α-(acetoxymethyl)benzylamino]-purine;

6-[α-(3-bromobenzoyloxymethyl)benzylamino]-purine;

6-[α-(trifluoromethyl)benzylamino]-purine;

6-[α-(carbamoyl)benzylamino]-purine;

6-[α-(carbomethoxy)benzylamino]-purine;

6-[α-(dimethylaminomethyl)benzylamino]-purine;

6-[α-(hydroxymethyl)-2-tetralylmethylamino]-purine;

6-[α-(acetoxymethyl)-2-tetralylmethylamino]-purine;

6-[α-(3-bromobenzoyloxymethyl)-2-tetralylmethylamino]-purine;

6-[α-(trifluoromethyl)-2-tetralylmethylamino]-purine;

4-[α-(carbamoyl)-2-tetralylmethylamino]-purine;

4-[α-(carbomethoxy)-2-tetralylmethylamino]-purine; ana

4-[α-(dimethylaminomethyl)-2-tetralylmethylamino]-purine;

either as single isomers or as a mixture thereof and thepharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a novel bicyclic4-aralkylaminopyrimidine derivative of formula (IB), or apharmaceutically acceptable salt thereof, as defined above, for use asan active therapeutic substance, in particular as tyrosine kinaseinhibitor.

Object of the invention is also a pharmaceutical composition comprisinga compound of formula (IB), or a pharmaceutically acceptable saltthereof, as defined above, as an active principle and a pharmaceuticallyacceptable excipient (which can be a carrier and/or diluent).

The compounds of formula (I), (IA), (IB) and the pharmaceuticallyacceptable salts thereof, are altogether defined hereafter as the"compounds of the invention" or as the "active agents" of the invention.

The novel compounds of formula (IB) and the known ones of formula (I)and (IA) can be similarly obtained by the same analogy process. Forinstance the novel compounds of formula (IB) and the salts thereof canbe obtained by a process comprising the condensation of a compound offormula (II) ##STR5## wherein A, R₁ and R₂ are as defined above and L isa leaving group with an amine compound of formula (III) ##STR6## whereinB, R, R₃ and R₄ are as defined above; and, if desired, converting acompound of formula (IB) into another compound of formula (IB), and/or,if desired, converting a compound of formula (IB) into a salt thereof,and/or, if desired, converting a salt of a compound of formula (IB) intoa free compound of formula (IB), and/or, if desired, separating amixture of isomers of a compound of formula (IB) into the singleisomers.

A leaving group in a compound of formula (II) is for instance chloro,methylthio and 1,2,4-triazol-1-yl.

The reaction of a compound of formula (II) wherein L is chloro with acompound of formula (III) is an analogy process, which can be carriedout using known methods, e.g. as described by Bullock et al. inJ.Am.Chem.Soc. 78, 3693 (1956). The reaction is carried out in thepresence of a suitable inert organic solvent, for example an alkanol orester such as methanol, ethanol, isopropanol, methyl cellosolve or ethylacetate, a halogenated solvent such as dichloromethane or chloroform, anether such as tetrahydrofuran or dioxane, a dipolar aprotic solvent suchas dimethylformamide or dimethylacetamide. Preferably the solventsisopropanol or methyl cellosolve are used. The reaction is convenientlycarried out at a temperature in the range from about 10 to about 150°C., preferably in the range from about 20 to about 80° C. In generalonly 1 equivalent of amine compound (III) is used, thus giving thehydrochloride salt, which precipitates on cooling. To obtain the freebase of the compound of formula (IB) from the salt, the salt may betreated with a suitable base in the presence of an appropriate solventsuch as the ones mentioned above. Suitable bases are e.g. organic aminessuch as triethylamine or pyridine, or inorganic bases such as sodiumcarbonate or sodium hydroxide. Alternatively to obtain directly the freebase of formula (IB) one may apply more than 2 equivalent of aminecompound (III) in the reaction.

The reaction of a compound of formula (II), wherein L is1,2,4-triazol-1-yl, with a compound of formula (III) can be carried outaccording to known methods, e.g. as described in EP 0414386.Accordingly, about 1 molequivalent of triazolyl compound II and about 1molequivalent of amine compound (III) is reacted at reflux temperaturein an inert organic solvent such as chloroform, methylenechloride,benzene or toluene. After about 2 h an organic base such triethylamineis added and the reflux is continued for about 2 h.

The optional salification of a compound of formula (IB) as well as theconversion of the salt into the corresponding free compound and theseparation of the mixture of isomers into the single isomers as well asthe conversion of a compound of formula (IB) into another compound offormula (IB) may be carried according to known methods.

The conversion of a compound of formula (IB), wherein R₁ or R₂ ishalogen, into a compound of formula (IB), wherein R₁ or R₂ is NR₅ R₆,can be carried out by known methods, e.g. according to the method ofBullock et al [J.Am.Chem.Soc. 78,3693 (1956)] as described above.

The conversion of a compound of formula (IB), wherein R₁ or R₂ ishalogen, into a compound of formula (IB), wherein R₁ or R₂ is C₁ -C₄alkoxy, can be carried out by using known methods. For example to obtainthe C₁ -C₄ alkoxy derivative, the corresponding halogen derivative isreacted with an alkali C₁ -C₄ alkanoate (prepared by adding an alkalimetal to the corresponding C₁ -C₄ alkanol) in C₁ -C₄ alkanol solution attemperatures ranging from about 50 to about 100° C. in a pressurevessel.

The conversion of a compound of formula (IB) wherein R is hydroxy-(C₁-C₄)alkyl into a compound of formula (IB) wherein R is (C₂-C₄)acyloxy-(C₁ -C₄)alkyl or halobenzoyloxy-(C₁ -C₄) alkyl, can becarried out by using known methods, e.g. by reaction with a reactivederivative of a suitable carboxylic acid, such as an anhydride orhalide, in the presence of a basic agent, at temperatures ranging fromabout 0 to about 50° C. Preferably the acylation is carried out byreaction with the respective acid anhydride or chloride in the presenceof an organic base such as pyridine.

The conversion of a compound of formula (IB) wherein R is hydroxy-(C₁-C₄)alkyl into a compound of formula (IB) wherein R is (C₁-C₄)alkoxy-(C₁ -C₄)alkyl, can be carried out by known methods. Accordingto the Williamson reaction (for a review see Patai: The chemistry of theether linkage, Interscience Publisher NY 1967) the alcohol is firsttransformed into alkali metal alkoxide, preferably by reaction withsodium hydride, which is then reacted with an (C₁ -C₄)alkylhalide,preferably an (C₁ -C₄)alkyliodide, in an inert organic solvent such asbenzene.

The conversion of a compound of formula (IB) wherein R is halo-(C₁-C₄)alkyl into a compound of formula (IB) wherein R is (C₁-C₄)alkylamino-(C₁ -C₄)alkyl, can be carried out by known methods, e.g.as described in Houben-Weyl, Methoden der Organischen Chemie, volumeXI/1, page 24(1957). Accordingly, the halocompound, preferably a iodo orbromine compound, is reacted with an (C₁ -C₄)alkylamine (preferablyusing an excess) in an inert solvent such as water or alkohol attemperatures ranging from about 0 to about 100° C.

A compound of formula (IB) wherein R is (C₁ -C₄) alkoxycarbonyl-(C₁-C₄)alkyl can be obtained by conversion (esterification) of a compoundof formula (IB) wherein R is carboxy-(C₁ -C₄)alkyl by using knownmethods, e.g. as described in Houben-Weyl: Methoden Organischen ChemieVIII, 508 (1952). Thus the acid compound is reacted with an excess of an(C₁ -C₄)alcohol in an inert solvent such as chloroform or benzene attemperatures ranging from room to reflux temperatures in the presence ofa mineral acid catalyst such as sulfuric or hydrochloric acid.

The conversion of a compound of formula (IB) wherein R is a (C₁-C₄)alkoxycarbonyl-(C₁ -C₄)alkyl, preferably carbomethoxy-(C₁ -C₄)alkyl,into a compound of formula (IB) wherein R is carbamoyl-(C₁ -C₄)alkyl,may be carried out by aminolysis, e.g. as described in Houben-Weyl:Methoden der Organischen Chemie, volume E5, part 2, page 983 (1985).

The compounds of formula (II) are known or may be obtained by knownmethods from known compounds. For example the 4-chloro compound offormula (II) wherein L is chloro is prepared by chlorodehydroxylation ofthe corresponding 4-hydroxypyrimidine derivative of formula (IV)##STR7## wherein A, R₁ and R₂ are as defined above, by usingconventional methods, e.g. by reaction with POCl₃ or SOCl₂. For examplethe preparation of 4-chloro-6,7-dimethoxyquinazoline from4-hydroxy-6,7-dimethoxyquinazoline is described in example 1 of patentAU9331010.

The intermediate of formula (II), wherein L is 1,2,4-triazol-1-yl, canbe prepared, e.g. by adding gradually POCl₃ to a mixture of compound(IV) (1 equivalent) and 1,2,4-triazole (3 equivalent) in pyridinesolution at a temperature ranging from room to reflux temperature.

The compounds of formula (IV) are commercially available or may beobtained by known methods from known compounds. A general applicablemethod for the synthesis of compounds of formula (V) in which A isbenzene is to condense an anthranilic acid derivative of formula (V):##STR8## wherein R₁ and R₂ are as defined above, with an excess offormamide at temperatures ranging from 170 to 200° C. The compounds offormula (V) are known or may be obtained by known methods from knowncompounds.

When in the new compounds of the present invention and in theintermediate products used for their preparation there are groupspresent which need to be protected before the above-described reactionsare performed, they may be protected before the reaction takes place andthen deprotected at the end of the reaction, according to well knownmethods in organic chemistry.

Pharmacology

The compounds of the invention possess specific tyrosine kinaseinhibiting activity. It is believed that tyrosine kinase inhibitors maybe of great importance in the control of uncontrolled cellularreproduction, i.e. in cellular reproduction disorders. Hence, thecompounds according to the present invention can be useful in thetreatment of pathological proliferation disorders in mammals, includinghumans. Typical examples of such disorders are tumors, includingleukemia, and psoriasis. The compounds of the invention can also beuseful in inhibiting the development of the atheromatous plaque and inthe control of angiogenesis and as anti-metastatic agents.

Recent studies on the molecular basis of the neoplastic transformationhave identified a family of genes, designed oncogenes, whose aberrantexpression causes tumorigenesis. For example, the RNA tumor virusespossess such an oncogene sequence whose expression determines neoplasticconversion of infected cells. Several of their oncogene-encodedproteins, such as pp₆₀ ^(v-src), p70^(gag-yes), p130^(gag-fps) and p₇₀^(gag-fgr) display protein tyrosine kinase activity, that is theycatalyze the transfer of the γ-phosphate from adenosine triphosphate(ATP) to tyrosine residues in protein substrate. In normal cells,several growth factor receptors, for example the receptors for PDGF,EGF, α-TGF and insulin, display tyrosine kinase activity. Binding of thegrowth factor (GF) activates the receptor tyrosine kinase to undergoautophosphorylation and to phosphorylate closely adjacent molecules ontyrosine. Therefore, it is thought that the phosphorylation of thesetyrosine kinase receptors plays an important role in signal transductionand the principal function of tyrosine kinase activity in normal cellsis to regulate cell growth. Perturbation of this activity by oncogenictyrosine kinases that are either overproduced and/or display alteredsubstrate specificity may cause loss of growth control and/or neoplastictransformation. Accordingly, a specific inhibitor of tyrosine kinase canbe useful in investigating the mechanism of cancerogenesis, cellproliferation and differentiation and it can be effective in theprevention and chemotherapy of cancer and in other pathologicalproliferative conditions.

Hence the compounds according to the present invention can be useful inthe treatment of pathological proliferation disorders in mammals,including humans.

A human or animal, e.g. a mammal, can thus be treated by a methodcomprising the administration thereto of a therapeutically effectiveamount of one of the compounds of the invention. In this way thecondition of the human or animal may be improved. Amelioration of thedisease state or disorder from which the human or animal is sufferingcan be achieved. Typical examples of such disorders are benign andmalignant tumours, including leukemia such as myeloblastic leukaemia,lymphoma, sarcoma, neuroblastoma, Wilm's tumour, malignant neoplasm ofthe bladder, breast, lung or thyroid, neoplasias of epithelial origin,such as mammacarcinoma. Moreover, they can be useful in the treatment ofepidermal hyperproliferation, such as psoriasis. The compounds of theinvention can also be useful in inhibiting the development of theatheromatous plaque and restenosis, in the control of angiogenesis, asanti-metastatic agents and in treating diabetic complications. They havealso utility in the control of immune system diseases, e.g. asimmunosuppressants, as far as protein tyrosine kinases, particularlyZap70, p56 lck and p59 fyn, are strongly involved in the control of theproliferation of the immune system. Moreover, the compounds of theinvention have utility in the treatment of Alzheimer's disease due tothe pivotal role played by tyrosine phosphorylation (e.g. Tau proteins)in the development of the disease.

The tyrosine specific protein kinase activity of the compounds of theinvention is shown, e.g., by the fact that they are active in the invitro and in vivo test described herebelow.

EGFR-Autophosphorylation Assay (AMIKA assay)

The EGFR autophosphorylation was assayed using A431 crude membraneextracts as source of the receptor.

Membrane purification:

Membranes were prepared as reported by A. Levitzky et al. (Methods inEnzymology 201, 347 (1991) with minor modifications and adapting themethod to the A431 human epidermoid carcinoma cell line. Briefly, lowdensity cells growing in RPMI 1640 plus 10% foetal calf serum weredetached using 1 mM EDTA in phosphate buffer saline (PBS) and lysed incold Lysing buffer (1 ml/10⁶ cells) (20 mM HEPES pH 7.6, 10 mM NaCl, 2mM EDTA, 10 mg/ml Aprotinin, 10 mg/ml Luepeptin, 1 mM PMSF). Cells werehomogenized by 10 strokes in Dounce homogenizer. Nuclei and debris wereremoved by low speed centrifugation. Membranes were pelletized byultracentrifugation (1 h, 100000×g) and resuspended in cold HNG buffer(50 mM HEPES pH 7.6, 125 mM NaCl, 10% glycerol). Protein concentration,determined by Pierce BCA method, was adjusted to 1.5-2 mg/ml. Aliquotswere stored at -80° C.

Determination of IC₅₀ :

To determine the IC50 A431 membranes (2.5 mg of protein/sample)pre-treated with EGF (final concentration 200 nM) for 30 min at 4° C.were incubated in 30 ml of reaction buffer (50 mM HEPES pH 7.6, 125 mMNaCl, 12 mM Mg-acetate, 2 mM MnCl₂, 1 mM NaVO₃, 1 mM ATP, 1 mCi γ-³²P-ATP) for 1 min at 0° C. in the presence of increasing concentrationsof compounds. The reaction was stopped with Laemly solution. The sampleswere heated 5 min at 95° C. and submitted to SDS-PAGE (7.5% acrylamidegel). Gels were fixed in 40% methanol:10% acetic acid for 1 h and washedovernight with 20% methanol:7% acetic acid. After 15 min in 50%methanol:2% glycerol gels were dried and exposed overnight. Bandscorresponding to EGFR were excised from the gels and counted in aβ-counter.

Inhibition of cellular tyrosine autophosphorylation (VAP assay)

EGF is able to induce the phosphorylation in tyrosine of a specific setof intracellular proteins including EGFR itself. This increase intyrosine phosphorylation was measured using the Vectastain-ABC-AP kit(Vector Laboratories) following the manufacturer's instructions.Briefly, 2×10⁴ A431 cells per well were plated into a microtiter plateand incubated for 3 days at 37° C./5% CO₂ until the cultures reachedconfluency. Cell monolayers were washed with PBS and covered with freshmedium containing 0.1 bovine serum albumin (BSA). Serial dilution oftest compounds were added 2 h before the addition of 100 ng/ml EGF;after 10 min stimulation the culture medium was withdrawn, cells werewashed 2 times with PBS and fixed for 10 min with cold methanol (-20°C.). After fixation 200 ml of blocking solution (3% BSA in PBS, 0.2%Tween 20, 1% normal horse serum) were added for 1 h at 37° C. Blockingsolution was replaced with 3% BSA in PBS containing theantiphosphotyrosine antibody 4G10 (UBI) diluted 1:30000 and incubatedfor 1 h. Bound antibodies were revealed using the Vectastain-ABC-AP kitwith p-nitrophenyl phosphate as the substrate. Reaction was developedfor 30 min in the dark and the plates were read at 405 nm.

SRB-Antiproliferative assay (A431 assay)

The antiproliferative activity of the test compounds was assayed on A431cells using the SRB colorimetric method (P. Skehan et al. :J.Natl.Cancer Inst.1990, 82, 1107-1112). A431 cells were seeded into96-well microtiter plates (5000 cells/cm²) and incubated overnight at37° C./5% CO₂. Compounds dissolved in DMSO were added in serial dilutionand plates were incubated for 3 days at 37° C./5% CO₂. Cells were fixedwith cold TCA (10% final concentration) and stained with 0.4%Sulforhodamine B dye in 1% acetic acid for 30 min. Dye was solubilizedwith 10 mM Tris (pH 10.4) and microtiters were read at 550 nm.

The inhibitory activity data for a representative group of compoundsaccording to the present invention, obtained by the AMIKA-, VAP- andA431-assay as described above, are set out in the following Table 1.

                  TABLE 1                                                         ______________________________________                                        AMIKA                                                                           % of inhibition at VAP A431                                                 FCE    1 μM 10 μM                                                                              IC.sub.50  (μM)                                                                    IC.sub.50  (μM)                                                                    IC.sub.50  (μM)                     ______________________________________                                        29771  93.8    98.3    0.024   0.8     >1.56                                    29772 94.9 98 0.081 1.31 5.3                                                ______________________________________                                    

FCE 29771 means(S)-4-[α-(hydroxymethyl)benzylamino]-6,7dimethoxyquinazoline; and

FCE 29772 means(S)-4-[α-(acetoxymethyl)benzylamino]-6,7dimethoxyquinazoline.

As can be appreciated from the activity data shown in Table 1, thecompounds according to the invention are endowed with valuablebiological properties.

In view of their high activity, the compounds of the invention can beused safely in medicine.

The compounds of the invention can be administered in a variety ofdosage forts, e.g. orally, in the forms of tablets, capsules, sugar- andfilm-coated tablets, liquid solutions or suspensions; rectally, in theform of suppositories; parenterally, e.g. intramuscularly, or byintravenous injection or infusion; or topically. The dosage depends onthe age, weight, condition of the patient and administration route. Forexample, the dosage adopted for oral administration to adult humans forthe compound 4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazolinemay range from about 5 to about 150-200 mg per dose, from 1 to 5 timesdaily. Of course, these dosage regimes may be adjusted to provide theoptimal therapeutic response.

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the activecompound, diluents, e.g. lactose, dextrose, saccharose, cellulose, cornstarch or potato starch; lubricants, e.g. silica, talc, stearic acid,magnesium or calcium stearate, and/or polyethylene glycols; bindingagents, e.g. starches, arabic gums, gelatin, methylcellulose,carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents,e.g. a starch, alginic acid, alginates or sodium starch glycolate,effervescing mixtures; dyestuffs;

sweeteners; wetting agents, such as lecithin, polysorbates,laurylsulphates; and, in general, non-toxic and pharmacologicallyinactive substances used in pharmaceutical formulations. Saidpharmaceutical preparations may be manufactured in known manner, bymeans of mixing, granulating, tabletting, sugar-coating or film-coatingprocesses.

The liquid dispersion for oral administration may be, e.g., syrups,emulsions and suspensions.

The syrup may contain as carrier, for example, saccharose or saccharosewith glycerine and/or mannitol and/or sorbitol. The suspensions and theemulsions may contain as carrier, for example, a natural gum, agar,sodium alginate, pectin, methylcellulose, carboxymethylcellulose orpolyvinyl alcohol. The suspensions or solutions for intramuscularinjections may contain, together with the active compound, apharmaceutically acceptable carrier, e.g. sterile water, olive oil,ethyl oleate, glycols, e.g. propylene glycol, and, if desired, asuitable amount of lidocaine hydrochloride. The solutions forintravenous injections or infusions may contain as carrier, for example,sterile water or, preferably, they may be in the form of sterileaqueous, isotonic saline solutions.

The suppositories may contain, together with the active compound, apharmaceutically acceptable carrier, e.g. cocoa-butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

Compositions for topical application, e.g. creams, lotions or pastes,can be prepared by admixing the active ingredient with a conventionaloleaginous or emulsifying excipient.

A further object of the present invention is a combined method oftreatment of cancer or of amelioration of the conditions of mammals,including humans, suffering from cancer, said method comprisingadministering

1) a compound of the invention, that is a compound of formula (I), (IA)or (IB) or a pharmaceutically acceptable salt thereof, and

2) an additional antitumor agent, in amounts and close enough togetherin time sufficient to produce a therapeutically useful effect.

The present invention also provides products containing a compound ofthe invention, that is a compound of formula (I), (IA) or (IB) or apharmaceutically acceptable salt thereof, and an additional antitumoragent as a combined preparation for simultaneous, separate or sequentialuse in anticancer therapy.

The term "antitumour agent" is meant to comprise both a singleantitumour drug and "cocktails", i.e. a mixture of such drugs, accordingto the clinical practice.

Examples of antitumour agents that can be formulated with a compound ofthe invention or, alternatively, can be administered in a combinedmethod of treatment, include doxorubicin, daunomycin, epirubicin,idarubicin, etoposide, fluorouracil, melphalan, cyclophosphamide,bleomycin, vinblastin and mitomycin or a mixture of two or more thereof.The compounds of the invention can therefore be used in a treatment toameliorate a cancer. They may be administered to a patient sufferingfrom a cancer treatable with an antitumour agent, for example ananthracycline glycoside such as doxorubicin, daunomycin, epirubicin oridarubicin as mentioned above, together with the antitumour agent.

A compound of the invention and an antitumour agent such as ananthracycline glycoside can be administered to improve the condition ofa patient having leukemia such as myeloblastic leukemia, lymphoma,sarcoma, neuroblastoma, Wilm's tumour or malignant neoplasm of thebladder, breast, lung or thyroid. Accordingly, the present inventionprovides a method of treating a patient in need of a tyrosine kinaseinhibitor, the method comprising administering to said patient atherapeutically effective amount of a compound of formula (I), (IA) orof formula (IB), as defined above, or a pharmaceutically acceptable saltthereof.

The following examples illustrate but do not limit the invention.

EXAMPLE 1

(S)-4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline

A solution of 4-chloro-6,7-dimethoxyquinazoline (225 mg, 1 mmol),(S)-2-phenylglycinol (137.2 mg, 1 mmol) and triethylamine (304 mg, 3mmol) in isopropanol (7 ml) was heated to reflux for about 8 h. Then themixture was evaporated under vacuum to dryness and the residue purifiedby gradient elution chromatography on silica gel using as eluantdichloromethane/ethanol 2-6%. Thus pure title compound was obtained in70% yield (228 mg).

C₁₈ H₁₉ N₃ O₃ calcd: C66.45 H5.89 N12.91 found: C66.39 H5.81 N12.88

MS m/z 325

NMR δ ppm (DMSO-d₃): 3.79 (m, 2H), 3.87, 3.93 (two s, 6H) 4.96 (t, J=5.7Hz, 1H), 5.52 (m, 1H), 7.06 (s, 1H), 7.1-7.5 (m, 5H), 7.78 (s, 1H), 8.01(d, J=8.1 Hz, 1H), 8.24 (s, 1H).

According to the above described procedure the following compounds canbe prepared:

(R)-4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline

C₁₈ H₁₉ N₃ O₃ calcd: C66.45 H5.89 N12.91 found: C66.31 H5.75 N12.65

MS m/z 325

NMR δ ppm: 3.79 (m, 2H), 3.87, 3.93 (two s, 6H), 5.02 (t, J=5.7 Hz, 1H),5.52 (m, 1H), 7.06 (s, 1H), 7.1-7.5 (m, 5H) 7.78 (s, 1H), 8.05 (d, J=8.1Hz, 1H), 8.24 (s, 1H).

4-[α-(trifluoromethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbamoyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbomethoxy)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(dimethylaminomethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(hydroxymethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(trifluoromethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbamoyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(carbomethoxy)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

4-[α-(dimethylaminomethyl)-2-tetralylmethylamino]-6,7dimethoxyquinazoline;

(S)-6-[α-(hydroxymethyl)benzylamino]-purine

C₁₃ H₁₃ N₅ O calcd: C61.17 H5.13 N27.43 found: C61.05 H5.05 N27.35

MS m/z 255.

NMR δ ppm: 3.75 (m, 2H), 4.92 (t, J=5.0 Hz, 1H), 5.38 (m, 1H) 7.0-7.5(m, 5H), 7.77 (d, J=8.3 Hz, 1H), 8.10 (s, 2H), 12.9 (bs, 1H)

6-[α-(trifluoromethyl)benzylamino]-purine;

6-[α-(carbamoyl)benzylamino]-purine;

6-[α-(carbomethoxy)benzylamino]-purine;

6-[α-(dimethylaminomethyl)benzylamino]-purine;

6-[α-(hydroxymethyl)-2-tetralylmethylamino]-purine;

6-[α-(trifluoromethyl)-2-tetralylmethylamino]-purine;

4-[α-(carbamoyl)-2-tetralylmethylamino]-purine;

4-[α-(carbomethoxy)-2-tetralylmethylamino]-purine; and

4-[α-(dimethylaminomethyl)-2-tetralylmethylamino]-purine.

EXAMPLE 2

(S)-4-[α-(acetoxymethyl)benzylamino]-6,7-dimethoxyquinazoline

A solution of(S)-4-[α-(hydroxymethyl)benzylamino]-6,7dimethoxyquinazoline (70 mg,0.21 mmol) in acetic anhydride (2 ml) was stirred at room temperaturefor 3 h. Then water was added to the reaction mixture, the precipitatewas filtered, washed with water and dried under vacuum. Thus pure titlecompound was obtained in 90% yield (71 mg).

C₂₀ H₂₁ N₃ O₄ calcd: C65.38 H5.76 N11.44found: C65.18 H5.73 N11.45

MS m/z 367.

NMR δ ppm: 1.95 (s, 3H), 3.88, 3.93 (two s, 6H), 4.42 (m, 2H), 5.30 (m,1H), 7.09 (s, 1H), 7.2-7.5 (m, 5H), 7.73 (s, 1H), 8.15 (d, J=8.1 Hz,1H), 8.27 (s, 1H).

According to the above described procedure the following compounds canbe prepared:

4-[α-(acetoxymethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;

6-[α-(acetoxymethyl)benzylamino]-purine; and

6-[α-(acetoxymethyl)-2-tetralylmethylamino]-purine.

EXAMPLE 3

(S)-4-[α-(3-bromobenzoyloxymethyl)benzylamino]-6,7-dimethoxyquinazoline

To a solution of(S)-4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline (49 mg,0.15 mmol) in pyridine (2 ml) was added dropwise at 0-5° C.3-bromobenzoylchloride (33 mg, 0.15 mmol). After 6 h stirring at roomtemperature the reaction mixture was poured into iced water andextracted with dichloromethane. The organic layer was dried andevaporated to dryness. The residue was purified by flash chromatographyon silica gel using as eluant dichloromethane/methanol 95:5 to give puretitle compound as a white solid in 71% yield (54 mg).

C₂₅ H₂₂ BrN₃ O₄ calcd: C59.07 H4.36 Br15.72 N8.27found: C58.95 H4.15Br15.65 N8.21

MS m/z 508.

NMR δ ppm: 3.87, 3.91 (two s, 6H), 4.70 (m, 2H), 6.01 (m, 1H), 7.09 (s,1H), 7.2-7.6 (m, 7H), 7.73 (s, 1H), 7.81 (m, 1H), 7.90 (s, 1H), 8.23 (d,J=8.1 Hz, 1H), 8.28 (s, 1H).

According to the above described procedure the following compounds canbe prepared:

(R)-4-[α-(3-bromobenzoyloxymethyl)benzylamino]-6,7-dimethoxyquinazoline;

4-[α-(3-bromobenzoyloxymethyl)-2-tetralylmethylamino]-6,7dimethoxyquinazoline;

6-[cc-(3-bromobenzoyloxymethyl)benzylamino]-purine; and

6-[α-(3-bromobenzoyloxymethyl)-2-tetralylmethylamino]-purine.

EXAMPLE 4

(S)-4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazolinehydrochloride salt

To a solution of(S)-4-[α-(hydroxymethyl)benzylamino]-6,7dimethoxyquinazoline (325 mg, 1mmol) in ethanol (2 ml) was added 1N hydrochloric acid (2 ml, 2 mmol)and the resulting mixture was evaporated under vacuum to dryness to givepure title compound in about 100% yield.

C₁₈ H₂₀ ClN₃ O₃ calcd: C59.75 H5.57 C19.80 N11.61 found: C59.65 H5.51C19.75 N11.63

MS m/z 361.

EXAMPLE 5

(S)-4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline free base

A suspension of(S)-4-[α-(hydroxymethyl)benzylamino]-6,7dimethoxyquinazolinehydrochloride salt (361.8 mg, 1 mmol) and potassium carbonate (276 mg, 2mmol) in methanol (6 ml) was stirred at ambient temperature for 0.5 h.The mixture was filtered and the filtrate evaporated under vacuum. Theresidue was purified by column chromatography on silica gel (eluantdichloromethane/ethanol 2-6%) to give pure title compound in 90% yield.

EXAMPLE 6

4-chloro-6,7-dimethoxyquinazoline

A mixture of 4,5-dimethoxyanthranilic acid (1.97 g, 10 mmol) andformamide (1.0 ml, 25 mmol) was heated to 190° C. for 6 h understirring. Water (5 ml) was added after cooling to approximately 80° C.and the mixture was stored at room temperature for about 3 h. Theprecipitate was filtered, washed with water and dried to give6,7-dimethoxyquinazolin4-one in about 18% yield (0.370 g).

To the above obtained compound (0.370 g, 1.79 mmol) was added thionylchloride (4 ml) and DMF (1 drop) and the mixture was stirred and heatedto reflux for 2 h. After evaporation the mixture was partitioned betweenethyl acetate and saturated sodium bicarbonate solution. The organicphase was washed, dried and evaporated to dryness. The residue waspurified by column chromatography using increasingly polar mixture ofdichloromethane and ethyl acetate. There was thus obtained pure titlecompound in about 28% yield (0.113 g).

EXAMPLE 7

Tablets each weighing 0.150 g and containing 25 mg of the activesubstance, can be manufactured as follows:

Composition (for 10,000 tablets):

(S)-4-[α-(hydroxymethyl)benzylamino]-6,7dimethoxyquinazoline

Lactose 800 g

Corn starch 415 g

Talc powder 30 g

Magnesium stearate 5 g

The (S)-4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline, thelactose and half of the corn starch are mixed; the mixture is thenforced through a sieve of 0.5 mm mesh size. Corn starch (10 g) issuspended in warm water (90 ml) and the resulting paste is used togranulate the powder. The granulate is dried, comminuted on a sieve of1.4 mm mesh size, then the remaining quantity of starch, talc andmagnesium stearate is added, carefully mixed and processed into tablets.

EXAMPLE 8

Capsules, each dosed at 0.200 g and containing 20 mg of the activesubstance can be prepared.

Composition for 500 capsules:

(S)-4-[α-(acetoxymethyl)benzylamino]-6,7dimethoxyquinazoline 10 g

Lactose 80 g

Corn starch 5 g

Magnesium stearate 5 g

This formulation is encapsulated in two-piece hard gelatin capsules anddosed at 0.200 g for each capsule.

What is claimed is:
 1. A method for inhibiting tyrosine kinase in amammal comprising administering to said mammal a therapeuticallyeffective amount therefor of a pyrimidine compound of formula (I) or apharmaceutically acceptable salt thereof ##STR9## wherein A is a benzenering;B is a benzene, tetralin, indan or 2-oxindole ring; R is (C₁-C₄)perfluoroalkyl, phenyl, phenyl-(C₁ -C₄)alkyl, hydroxy-(C₁ -C₄)alkyl,(C₁ -C₄)alkoxy-(C₁ -C₄)alkyl, (C₂ -C₄)acyloxy-(C₁ -C₄)alkyl,halobenzoyloxy-(C₁ -C₄)alkyl, carboxy, carbamoyl, (C₁-C₄)alkoxycarbonyl, cyano, (C₁ -C₄)alkylcarbonyl, carboxy-(C₁ -C₄)alkyl,carbamoyl-(C₁ -C₄)alkyl, (C₁ -C₄)alkoxycarbonyl-(C₁ -C₄)alkyl, halo-(C₁-C₄)alkyl, amino-(C₁ -C₄)alkyl, mono- or di-(C₁ -C₄)alkylamino-(C₁-C₄)alkyl, sulfo-(C₁ -C₄)alkyl or sulfamido-(C₁ -C₄)alkyl; each of R₁and R₂, which may be the same or different, is hydrogen, C₁ -C₄ alkyl,C₁ -C₄ alkoxy, halogen or --NR₅ R₆ in which each of R₅ and R₆, which maybe the same or different is H or C₁ -C₄ alkyl; and each of R₃ and R₄,which may be the same or different, is hydrogen, C₁ -C₄ alkyl, halogen,hydroxy, C₁ -C₄ alkoxy, C₁ -C₄ alkoxycarbonyl, nitro, cyano or CF₃. 2.The method according to claim 1, wherein in the compound of formula (I)Bis a benzene or tetralin ring; R is hydroxy-(C₁ -C₄)alkyl, (C₂-C₄)acyloxy-(C₁ -C₄)alkyl, halobenzoyloxy-(C₁ -C₄)alkyl, (C₁-C₄)alkoxycarbonyl, di-(C₁ -C₄)alkylamino-(C₁ -C₄)alkyl, trifluoromethylor carbamoyl; each of R₁ and R₂, which may be the same or different, ishydrogen or C₁ -C₄ alkoxy; and each of R₃ and R₄ is hydrogen.
 3. Themethod according to claim 1, wherein the compound of formula (I) isselected from the group consistingof:4-[α-(hydroxymethyl)benzyilamino]-6,7-dimethoxyquinazoline;4-[α-(acetoxymethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(3-bromobenzoyloxymethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(trifluoromethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(carbamoyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(carbomethoxy)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(dimethylaminomethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(hydroxymethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;p14-[α-(acetoxymethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(3-bromobenzoyloxymethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(trifluoromethyl)-2-tetralylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(carbamoyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(carbomethoxy)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(dimethylaminomethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;and the pharmaceutically acceptable salts thereof; either as singleisomers or as a mixture thereof.
 4. A method for:treating epidermalhyperproliferation, as an anti-metastatic or anti-cancer agent, tocontrol angiogenesis, inhibit development of atheromatous plaque,treating Alzheimer's disease, or as an immunomodulating agent, in amammal, comprising administering to said mammal a therapeuticallyeffective amount of a pyrimidine compound of formula (IA) or apharmaceutically acceptable salt thereof ##STR10## wherein A is abenzene ring; B is a benzene, tetralin, indan or 2-oxindole ring; R is(C₁ -C₄)perfluoroalkyl, phenyl, phenyl-(C₁ -C₄)alkyl, hydroxy-(C₁-C₄)alkyl, (C₁ -C₄)alkoxy-(C₁ -C₄)alkyl, (C₂ -C₄)acyloxy-(C₁ -C₄)alkyl,halobenzoyloxy-(C₁ -C₄)alkyl, carboxy, carbamoyl, (C₁-C₄)alkoxycarbonyl, cyano, (C₁ -C₄)alkylcarbonyl, carboxy-(C₁ -C₄)alkyl,carbamoyl-(C₁ -C₄)alkyl, (C₁ -C₄)alkoxycarbonyl-(C₁ -C₄)alkyl, halo-(C₁-C₄)alkyl, amino-(C₁ -C₄)alkyl, mono- or di-(C₁ -C₄)alkylamino-(C₁-C₄)alkyl, sulfo-(C₁ -C₄)alkyl or sulfamido-(C₁ -C₄)alkyl; each of R₁and R₂, which may be the same or different, is hydrogen, C₁ -C₄ alkyl,C₁ -C₄ alkoxy, halogen or --NR₅ R₆ in which each of R₅ and R₆, which maybe the same or different is H or C₁ -C₄ alkyl; and each of R₃ and R₄,which may be the same or different, is hydrogen, C₁ -C₄ alkyl, halogen,hydroxy, C₁ -C₄ alkoxy, C₁ -C₄ alkoxycarbonyl, nitro, cyano or CF₃. 5.The method according to claim 4, wherein the compound of formula (IA)Bis a benzene or tetralin ring; R is hydroxy-(C₁ -C₄)alkyl, (C₂-C₄)acyloxy-(C₁ -C₄)alkyl, halobenzoyloxy-(C₁ -C₄)alkyl, (C₁-C₄)alkoxycarbonyl, di-(C₁ -C₄)alkylamino-(C₁ -C₄)alkyl, trifluoromethylor carbamoyl; each of R₁ and R₂, which may be the same or different, ishydrogen or C₁ -C₄ alkoxy; and each of R₃ and R₄ is hydrogen.
 6. Themethod according to claim 4, wherein the compound is selected from thegroup consistingof:4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(acetoxymethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(3-bromobenzoyloxymethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(trifluoromethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(carbamoyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(carbomethoxy)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(dimethylaminomethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(hydroxymethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline4-[α-(acetoxymethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(3-bromobenzoyloxymethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(trifluoromethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(carbamoyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(carbomethoxy)-2-tetrailylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(dimethylaminomethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;and the pharmaceutically acceptable salts thereof, either as singleisomers or as a mixture thereof or a pharmaceutically acceptable saltthereof.
 7. A pyrimidine compound of formula (IB) ##STR11## wherein A isa benzene ring;B is a benzene, tetralin, indan or 2-oxindole ring; R is(C₁ -C₄)perfluoroalkyl, phenyl, phenyl-(C₁ -C₄)alkyl, hydroxy-(C₁-C₄)alkyl, (C₁ -C₄)alkoxy-(C₁ -C₄)alkyl, (C₂ -C₄)acyloxy-(C₁ -C₄)alkyl,halobenzoyloxy-(C₁ -C₄)alkyl, carboxy, carbamoyl, (C₁-C₄)alkoxycarbonyl, cyano, (C₁ -C₄)alkylcarbonyl, carboxy-(C₁ -C₄)alkyl,carbamoyl-(C₁ -C₄)alkyl, (C₁ -C₄)alkoxycarbonyl-(C₁ -C₄)alkyl, halo-(C₁-C₄)alkyl, amino-(C₁ -C₄)alkyl, mono- or di-(C₁ -C₄)alkylamino-(C₁-C₄)alkyl, sulfo-(C₁ -C₄)alkyl or sulfamido-(C₁ -C₄)alkyl; each of R₁and R₂, which may be the same or different, is hydrogen, C₁ -C₄ alkyl,C₁ -C₄ alkoxy, halogen or --NR₅ R₆ in which each of R₅ and R₆, which maybe the same or different is H or C₁ -C₄ alkyl; and each of R₃ and R₄,which may be the same or different, is hydrogen, C₁ -C₄ alkyl, halogen,hydroxy, C₁ -C₄ alkoxy, C₁ -C₄ alkoxycarbonyl, nitro, cyano or CF₃ ; andwith the proviso that wherein when at the same time, A is unsubstitutedbenzene, R is hydroxy (C₁ -C₂)alkyl, (C₁ -C₄)alkoxy-(C₁ -C₂)alkyl or (C₂-C₄)acyloxy-(C₁ -C₂)alkyl, and B is phenyl, then at least one of R₃ andR₄ is other than hydrogen, halogen, C₁ -C₄ alkyl or C₁ -C₄ alkoxy.
 8. Acompound according to claim 7 selected from the group consistingof:4-[α-(hydroxymethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(acetoxymethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(3-bromobenzoyloxymethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(trifluoromethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(carbamoyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(carbomethoxy)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(dimethylaininomethyl)benzylamino]-6,7-dimethoxyquinazoline;4-[α-(hydroxymethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(acetoxymethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(3-bromobenzoyloxymethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(trifluoromethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(carbamoyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(carbomethoxy)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;4-[α-(dimethylaminomethyl)-2-tetrallylmethylamino]-6,7-dimethoxyquinazoline;andthe pharmaceutically acceptable salts thereof; either as singleisomers or as a mixture thereof or a pharmaceutically acceptable saltthereof.
 9. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and/or diluent and as an active principle a compoundas defined in claim
 7. 10. A process for the preparation of a compoundas defined in claim 7, comprising the condensation of a compound offormula (II) ##STR12## wherein A, R₁ and R₂ are as defined in claim 7and L is a leaving group with an amine compound of formula (III)##STR13## wherein B, R, R₃ and R₄ are as defined in claim 7; and, ifdesired, converting a compound of formula (IB) into another compound offormula (IB), and/or, if desired, converting a compound of formula (IB)into a salt thereof, and/or, if desired, converting a salt of a compoundof formula (IB) into a free derivative of formula (IB), and/or, ifdesired, separating a mixture of isomers of a compound of formula (IB)into the single isomers.